(944) Clinical exome and genome sequencing utility in non-isolated Dandy-Walker malformation evaluation: A retrospective analysis

Dandy-Walker malformation (DWM) is a rare congenital abnormality of the posterior fossa and the cerebellum, with an incidence of 1 in 10,000 to 30,000 births. DWM is commonly non-isolated and is associated with other central nervous system (CNS) abnormalities or extra-CNS anomalies (DWM+). Chromosomal abnormalities are known to be one of the causes of DWM+, however, single nucleotide variant (SNV) testing has not been widely assessed.  This work aims to assess the utility of SNV testing in the evaluation of DWM+

Study Design:

We retrospectively reviewed genetic testing results for individuals with DWM+ undergoing exome or genome sequencing at a tertiary center genetics reference lab between 2012-2025. Age ranged from fetal life - 29 years old. Postnatal median age at diagnosis was 1.19 years old. The primary outcome measure was the rate of diagnosis of exome/genome sequencing in DWM+

Results:

We analyzed the molecular data of 94 patients with DWM+, and a definitive or possible diagnosis was achieved for 47 individuals, yielding a diagnostic efficacy of 50%. Of these, 23 (48.9%) were a definitive diagnosis and 24 (51%) were possible. We identified several pathogenic variants in genes known to be associated with DWM+, such as CHD7, TUBA1A, TUBB, FKRP, and TMEM138. Our findings are consistent with the previously described association between ciliopathies and DWM; however, we provide substantial new evidence that elucidates the diagnosis of specific ciliopathies, which was previously under-reported in DWM. We also identified pathogenic variants in other genes that are infrequently considered in the evaluation of DWM+, such as ARID1A, ANKRD11, COL4A1, DDX3X, KMT2D (Kabuki), SMARCB1 (Coffin-Siris), and KRAS (Noonan).

Conclusion:

DWM+ is a complex phenotype with various etiologies; these results suggest that the use of exome/genome sequencing can improve the diagnostic rate and shorten the diagnostic odyssey. Furthermore, these findings can also guide providers and expectant parents in making informed decisions about prenatal diagnostic testing.